Nitrated Fatty Acids, Novel Anti-inflammatory Mediator in Allergic Airway Disease

硝化脂肪酸，过敏性气道疾病的新型抗炎介质

基本信息

批准号：
8448650
负责人：
RAJU C REDDY
金额：
$ 31.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448650
关键词：
Ablation Agonist Air Allergens Allergic Animal Model Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Biological Bronchoalveolar Lavage Fluid Chemicals Combined Modality Therapy Cyclic AMP Cyclic GMP Data Development Disease Epithelial Cells Fatty Acids Feedback Gene Silencing Genetic Genetically Engineered Mouse Human In Vitro Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Interleukin-17 Interleukin-4 Investigation Knock-out Lead Ligands Liquid substance Lung Lung Inflammation Lung diseases Measures Mediating Modeling Mucins Mucous body substance Mus New Agents Nitrates Nitric Oxide Nitric Oxide Synthase Nuclear Nuclear Receptors Peroxisome Proliferator-Activated Receptors Physiological Plasma Play Process Production Protein Isoforms Public Health Reaction Research Role Serum Severities Side Signal Pathway Staging TNF gene Testing Unsaturated Fatty Acids Urine Validation airway hyperresponsiveness allergic airway disease allergic response cell type chemokine cockroach allergen compound 30 cytokine in vivo inhibitor/antagonist novel novel strategies novel therapeutics overexpression public health relevance response transcription factor

项目摘要

ABSTRACT Asthma is a highly prevalent airway disease that is a major public health problem for which available treatment options are inadequate. Endogenous nitrated fatty acids (NFAs), thought to be produced from NO, have recently been identified as important bioactive compounds present in human plasma. Although investigation of their biological activities is at an early stage, evidence is accumulating that they are potent anti-inflammatory molecules. Our preliminary data show that administration of exogenous NFAs can significantly attenuate pathophysiologic manifestations in a murine model of allergic airway disease, whereas inhibiting endogenous NFA synthesis exacerbates allergic responses. NFAs activate the nuclear transcription factor peroxisome proliferator-activated receptor-¿ (PPAR-¿) in some cell types, and we have found that allergic responses are exacerbated when PPAR-¿ is genetically eliminated but are attenuated by overexpression of PPAR-¿ in airway epithelial cells in vivo. Accordingly, we propose to test the hypothesis that activation of airway epithelial cell PPAR-¿ by nitrated fatty acids significantly suppresses the effects of allergic airway disease, including inflammation and mucus production. Our Specific Aims are: 1) to determine the extent to which NFAs modulate PPAR-¿ activity in the lung and the severity of murine allergic airway disease, for which we will use mice constitutively lacking all three isoforms of nitric oxide synthase (triple NOS knockout) and therefore expected to lack NFAs; 2) to determine whether PPAR-¿ activation in airway epithelial cells mediates NFAs' ability to inhibit effects of allergen challenge in murine allergic airway disease, for which we will utilize mice with PPAR-¿ either knocked out or overexpressed selectively in airway epithelial cells; and 3) to determine whether NFAs inhibit chemokine and mucus production in cultured human airway epithelial cells and the extent to which these effects are mediated through PPAR-¿-dependent and/or PPAR-¿-independent mechanisms, for which we will use gene silencing and chemical inhibition to suppress PPAR-¿ while testing for activation of other signaling pathways. For Aims 1 and 2 we will utilize an established murine model of allergic airway disease induced by cockroach allergen, while Aim 3 will be carried out in vitro using well differentiated primary human bronchial epithelial cells grown at an air-liquid interface. Validation of our hypothesis will identify and elucidate the mechanisms through which a novel endogenous substance modulates the severity of allergic airway disease and may lead to new therapeutic avenues and treatments for asthma.

抽象的哮喘是一种非常普遍的气道疾病，是一个主要的公共卫生问题选项不足。内源性硝酸脂肪酸（NFA），被认为是由NO产生的最近被确定为人血浆中存在的重要生物活性化合物。虽然调查他们的生物学活动处于早期，有证据表明它们是潜在的抗炎分子。我们的初步数据表明，外源性NFA的给药可显着减弱过敏性气道疾病的鼠模型中的病理生理表现，而抑制内源性 NFA合成加剧了过敏反应。 NFA激活核转录因子过氧化素在某些细胞类型中，增生剂激活的受体 - （pPAR-€），我们发现过敏反应是当PPAR-被遗传消除时会加重，但通过气道中的PPAR-过表达抑制体内上皮细胞。彼此之间，我们建议检验气道上皮细胞激活的假设硝酸脂肪酸的PPAR-显着抑制了过敏性气道疾病的影响，包括炎症和粘液产生。我们的具体目的是：1）确定NFA调节的程度肺中的PPAR-活性和鼠过敏性气道疾病的严重程度，我们将使用小鼠组成性缺乏一氧化氮合酶的所有三种同工型（三个NOS敲除），因此有望缺乏NFA； 2）确定气道上皮细胞中的PPAR-激活是否介导NFA的抑制能力过敏原挑战在鼠过敏性气道疾病中的影响，我们将使用PPAR-®小鼠在气道上皮细胞中有选择性地撞倒或过表达； 3）确定NFA是否抑制培养的人类气道上皮细胞中的趋化因子和粘液产生效应是通过依赖性和/或pPAR-依赖性机制来介导的，我们将为此我们使用基因沉默和化学抑制作用来抑制PPAR-在测试其他信号传导时途径。对于目标1和2，我们将利用由既定的过敏气道疾病模型蟑螂过敏原，而AIM 3将在体外使用良好分化的原代人支气管进行体外进行在空气界面生长的上皮细胞。我们假设的验证将确定并阐明新型内源物质调节过敏性气道疾病的严重程度的机制并可能导致新的治疗途径和哮喘治疗方法。